The pathogenesis of the dopamine (DA) neuron degeneration that produces parkinsonian symptoms remains unknown, although recent Branch research appears to provide a partial explanation and point to a novel approach to neuroprotective therapy. In recently completed studies, we exposed SH-SY5Y cells, a human dopaminergic cell line, to the complex I inhibitor rotenone. Dose dependent apoptosis was preceded by the nuclear translocation of NF-kappaB followed by activation of caspase-3. PGA1, which increased the expression of HSP 70 and HSP 27, protected against rotenone-induced apoptosis without increasing necrotic death. PGA1 treatment blocked the rotenone-induced nuclear translocation of NF-kappaB and attenuated, but did not abolish the caspase-3 elevation. Unexpectedly, a caspase-3 inhibitor, at a concentration that completely prevented the caspase-3 increase produced by rotenone, failed to protect against apoptosis. These results suggest that complex I deficiency in dopaminergic cells can induce apoptosis by a process involving early NF-kappaB nuclear translocation and caspase-3 activation. PGA1 thus appears to protect against rotenone-induced cell death by inducing certain heat shock proteins (HSPs) and blocking the nuclear translocation of NF-kappaB in a process that attenuates caspase-3 activation but is not mediated by its inhibition. These findings suggested that drugs that stimulate PGA1 or HSP production could prove useful in the treatment of PD. Related Section investigations focused on the neuronal protein alpha-synuclein, implicated in the pathogenesis of PD and other neurodegenerative disorders. Earlier studies have reported that alpha-synuclein expression is restricted to neuronal presynaptic terminals, although this protein aggregates in Lewey bodies in somata that are distant from their axonal terminals. Little attention has been paid to this paradox and no compelling explanation proposed for the apparent discrepancy between the locus of alpha-synuclein expression and the loci of Lewey bodies. We explored this issue using various antibodies to map the distribution of alpha-synuclein throughout rat and human brain. In contrast to most previous reports, alpha-synuclein was detected by The monoclonal antibody Synuclein-1 in several brain regions in neuronal somata and dendrites as well as more ubiquitously in axons and terminals. Strongest alpha-synuclein neuronal expression was found in regions prone to Lewey body formation. Differences in antibody recognition of the multiple endogenous forms of alpha-synuclein could provide critical insight into determining whether various forms of this protein are differentially vulnerable to aggregation and neurotoxicity. Current treatments for Parkinson?s disease eventually fail, in large part due to the appearance of motor response complications. Earlier Section research suggested that the motor complications associated with the chronic nonphysiologic stimulation of dopaminergic receptors on striatal spiny neurons alters the sensitivity of nearby ionotropic glutamatergic receptors. Medium spiny neurons also express receptors for various nondopaminergic and non-glutamatergic neurotransmitters that have the potential for influencing their function, especially those that signal via serine/threonine kinases abarently activated by the nonphysiologic DA receptor stimulation associated with denervation and intermittent stimulation. Among such cell surface receptors are those of the serotonin 5HT2A type, which can activate protein kinase PKC (PKC). To address the possibility that 5HT2A receptor blockade can normalize pathologically activated PKC, we initiated animal model studies of the largely 5HT2A/C antagonist, quetiapine. Given alone to parkinsonian rats, quetiapine reversed the shortening in response produced by levodopa. Moreover, cotreatment with this atypical neuroleptic acted prophyllactically to prevent onset of the levodopa-induced shortening in motor response duration. Since 5HT2A receptor stimulation activates PKC signaling, we also evaluated the effect of quetiapine on the rise in AMPA receptor S831 GluR1 subunit phosphorylation associated with the appearance of levodopa-induced motor response alterations. Our results suggest a concomitant attenuation in both the levodopa-induced shortening in response duration and in the hyperphosphorylation of spiny neuron GluR1 subunits. In parkinsonian primates we found that quetiapine inhibited levodopa-induced dystonic as well as choreiform dyskinesias at a dose that had no effect on the antiparkinsonian response to levodopa. These promising findings have stimulated clinical studies of this and other 5HT2A antagonists. Among cell surface receptors expressed on striatal medium spiny neurons are those of the adenosine A2a type. Mainly located on D2 DA receptor bearing spiny neurons, A2a receptors also appear to signal, in part, through PKC activation and thus could influence AMPA receptor regulation. To evaluate the possibility that the effects of A2a receptor blockade in parkinsonian animals reflect changes which involve the phosphorylation state of striatal dendritic AMPA GluR1 subunits, the Section first initiated studies in levodopa treated parkinsonian rats. The results indicate that the selective A2a receptor antagonist KW-6002 can concomitantly reverse both the levodopa-induced motor response alterations and the associated S831 phosphorylation augmentation of striatal AMPA receptor GluR1 subunits. Studies then proceeded to the parkinsonian nonhuman primate. KW-6002 administered alone reduced parkinsonian severity but induced no dyskinesias in our MPTP lesioned monkeys. Daily injections of apomorphine reversed parkinsonian signs in all animals and induced abnormal involuntary movement placebo-treated monkeys within 10 days. In contrast, KW-6002 cotreated monkeys did not evidence any dyskinesias. Following discontinuation of KW-6002 treatment, while daily apomorphine injections were continued, animals previously treated with KW-6002 manifested dyskinesias within 10 - 12 days. Taken together, our animal model findings are consistent with the hypothesis that blockade of A2a receptors can reduce or prevent levodopa-associated motor response alterations, in part by normalizing the PKC mediated GluR1 subunit hyperphosphorylation. Based on these results, the Section explored the possibility that adenosine A2a receptor blockade could benefit the motor complication syndrome in patients with advanced PD. Findings of the Section proof-of-concept evaluation appear in agreement with animal model results and support our hypothesis concerning the nature of the clinical effects of selective A2a receptor blockade on motor function in PD. The data suggest that KW-6002 potentiated the antiparkinsonian effects of levodopa, while the severity of dyskinesias and motor fluctuations fell substantially below levels produced by an equivalent antiparkinsonian dose of levodopa monotherapy. KW-6002 also prolonged the efficacy half-time of levodopa, thus reducing wearing-off fluctuations. These highly encouraging results will accelerate further efforts to exploit the Section medium spiny neuron strategy for the treatment of PD. Since spiny neurons are also the primary target of the neurodegenerative process in HD, sensitization of NMDA receptors on residual striatal neurons might be involved in the generation of Huntington type chrorea. To evaluate this possibility, the NMDA receptor antagonist amantadine was administered to individuals with genetically proven disease. Chorea scores declined without increasing parkinsonian signs. The results support our hypothesis that NMDA receptor supersensitivity contributes to the clinical expression of dyskinesias in HD and that selective antagonists at that site can safely confer palliative benefit.